Novel 2&#39;-amino-thiazolo steroids



United States Patent 3,404,206 NOVEL 2'-AMINO-THIAZOL0 STEROIDS Daniel Bertin, Montrouge, and Jacques Pei-rennet, Paris,

France, assignors to Roussel-UCLAE Paris, France, a

corporation of France v No Drawing. Filed July 21, 1966, Ser. No. 566,740

Claims priority, application France, July 23, 1965,

25,797; Oct. 21,-1965, 35,779

15 Claims. (Cl. 424241) The invention relates to novel 2-amino-thiazolo-[5',4'- 16,17]-A -estratetraenes of the formula wherein R is selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms and phenyl alkyl with 1 to 2 alkyl carbon atoms and to a process for their preparation. The invention also relates to novel antihypophysial compositions and to a method of curbing excessive hypophysial activity in warm blooded animals.

Takeda et a1. (Chem. Pharm. Bull. Tokyo, vol. 10, pp. ll7377, 1962) have described 2 amino thiazolo androstanes with a saturated A ring or a A -double bond such as compounds of the formula I l C-NH2 or nd HO i i but they do not indicate any physiological activity for the compounds. However, the compounds of Formula I have interesting pharmacological activity, particularly an important curbing action on the hypophysis and are, therefore, useful for the treatment of excessive amounts in the hypophysis of the F.S.H. factor (folliculo-stimulating hormone gonadotrope) due to castration or menopause, and generally in all of these cases where a curbing of the hypophysial gonadotrophines is desired.

The particular advantage of the novel amino thiazolo steroids of Formula I with regard to known products endowed with an anti-F.S.H. activity, resides in the fact that they possess only a slight estrogenic activity. The significance of these new compounds lies in the fact that they can be administered at the time of any ailments occurring during menopause. Although most of the usual hypo physial inhibitors are also endowed with estrogenic activity, such as stilbene derivatives, or with progestomimetic activity, such as norethynodrel, whose use is limited by the occurrence of undesirable secondary manifestations, such as hemorrhages or nausea, the compounds of Formula I can be utilized in large dosages without any fear that any of the drawbacks of the known compounds will appear.

It is an object of the invention to provide novel 2"- amino thiazolo-[5,4-16,17]-A -estratetraenes of Formula I.

3,404,206 Patented Oct. 1, 1968 It is another object of the invention to provide a novel process for the preparation of the 2-amino -thiazolo steroids of Formula I and a novel intermediate therefor.

It-is a further object of the invention to provide novel anti-hypophysial compositions.

It is an additional object of the invention to provide a novel method of curbing excessive hypophysial activity in warm-blooded animals.

These and other objects and advantages of the invention will become obvious from the following detailed description.

The novel 2' amino -thiazolo-[5',4'-16,17]-A estratetraenes of the invention have the formula wherein R is selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms and phenyl alkyl with 1 to 2 alkyl carbon atoms. Examples of R are alkyl radicals such as methyl, ethyl, propyl, n-butyl, etc., and phenylalkyl radicals such as benzyl and phenethyl.

The novel process for the preparation of 2-aminothiazolo [5,4' 16,17]-A -estratetraenes of Formula I comprises reacting a compound of the formula wherein R has the above definition and X is an aor fl-halogen selected from the group consisting of chlorine, bromine and iodine with thiourea in a lower alkanol having 1 to 8 carbon atoms to form the corresponding estratetraenes. X is preferably bromine or iodine and the lower alkanol is methanol, ethanol or tertiary butanol.

When the condensation reaction is effected in a primary lower alkanol with little stearic hinderance, such as methanol or ethanol, there is formed a corresponding 4-alkoxy intermediate (which is the 17 position of the steroid moiety) which can be isolated. This 3-OR-2-amino-4'- alkoXy 4',5 dihydro thiazolo [5,4 16,17]-A estratriene intermediate may be saponified under alkaline conditions, such as by sodium hydroxide in methanol or subjected to a thermal treatment under vacuum to form the 2'-amino-thiazolo of Formula I.

When R is a benzyl on the starting A -estratriene of Formula II, the resulting 2'-amino-thiazolo steroid of Formula I can be subjected to hydrogenolysis to regenerate the phenolic hydroxy in the 3-position which can then be converted into any other desired ether.

The novel anti-hypophysial compositions of the invention are comprised of at least one 2'-amino-thiazolo-[5', 4',l6,l7]-A -estratetraene of the formula wherein R is selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms and phenyl alkyl with 1 to 2 alkyl carbon atoms and a major amount of a pharmaceutical carrier. The compositions may be in the 3 form of injectable solution or suspensions, in ampules, in multiple dose fiacons, in the form of implants, tablets, coated tablets, sublingual tablets and suppos1tor1es prepared in the usual manner.

The novel method of the invention of inhibiting hypophysis in Warm-blooded animals comprises administering to the animals an effective amount of at least one 2'- amino-thiazolo-[,4-16,17] A -estratetraene of the formula an anhydrous gaseous 4 N hydrochloric acid solution in ether were added to the filtrate which was then vacuum filtered and washed with ether. The precipitate thus obtained was dissolved in 25 cc. of 25% aqueous ethanol and after 4 cc. of an N soda solution were introduced dropwis'e therein, crystallization'was initiated and the rhixturewas agitated at room temperature for 2 hours. Then, the reaction mixture was vacuum filtered, washed with 60% aqueous ethanol and dried to obtain 1.29 gm. of 3-methoxy-2'-amino-4'-ethoxy-4,5' di'hydrothiazolog I I N 5"4'46,17]-A -estratriene having a m l g POlIlt of 196197 C. The product was insoluble in water and l /C NH2 soluble in chloroform. Ultia-vzoletspectra (in ethanol) hmax 278 mp. 6:22.,200 R0 x 287 m e=20,200

. Analysis. C H O N S; molecular weight=386.55. wherein R is selected from the group consisting of hydrocalculated; 0, 35%; H, 7 81%;.N, 7.25%; S, 8.30%; gen, alkyl of 1 to 8 carbon atoms and phenyl alkyl with O Found: c, 673%; H N, 71%; S 79%; 1 to 2 alkyl carbon atoms. The said compounds may be 3 1 administered orally, perlingually, transcutaneously or This Compound is not described i the li rectally. The usual useful dose is between 0.03 to 0.4 step B: Preparation of g' hi l mg./kg. per dose and 0.08 to 0.8 mg./kg. pe y r the [5' 4' 16 17] 1,3,5(10),1G t t t U d an atmosadult, depending upon the mode of administration. phere of nitroggn, 880 mg of z' In the following examples there are described several ethOXy 4,5, dihydmthiazolo [534' 16,17] 1 preferred embodiments to illustrate the invention. Howestratriene were dissolved in 10 cc, f h l h t d t ever, it should be understood that the invention is not reflux and after 0.3 f a Sodium hydroxide l ti intended to be limited to the Specific embodiments was added thereto, reflux was maintained for /2 hour. Example I. Preparation of 3-methoxy-2-amino-thialhen the reactlon mlxture was dlluged 3 z gbg ZO1o [5,4, 1617] A1,3,5(1o),mestratetraene water, then cooled, vacuum filtere was e W1 0 aqueous ethanol and finally dried. The product was re- 100 of y' crystallized from anhydrous tetrahydrofuran to obtain 174cm. p p according to the process described by 675 mg. (a yield of 85%) of 3-methoxy-2-aminothia S. Johnson et V01 P 2005 zolo-[5',4-16,17]-A -estratetraene having a meltwere dissolved in 6 cc. of anhydrous tertiary butanol and in point of 289 C. and a specific rotation of M1 after 45 mg of thiourea were added, the resulting solu- +98t 2 ,=0 85% i pyridine). tiOH W35 TefluXed for 18 hours Then, 1116 solution was The product was colorles sand was insoluble in ethanol, concentrated to f its Volume and Ilfiutfalilfid y the very slightly soluble in alcohol and soluble in chloroform, addition of a few cc. of a saturated aqueous solution of tetrahydrofuran a d dimethylforrnamide. sodium bicarbonate, and finally water was addedaThen, Analysis. C H ON S; molecular weight=340.48. the solution was cooled, vacuum filtered, washed with Calculated: C, 70.55%; H, 7.1%; N, 8.23%; S, 9. 1%- water and dried and the residue thus formed was dis- Found; C, 70.2%; H, 7.0%; N, 7.9%; S, 9.5%. Solved in hot anhydrous rtitrdhydfofuf1n- Y adding The said product was also obtained by the following Water, dTOPWiSE, and y i g crystallilation, procedure. mg. of 3-methoxy-Z'-amino-4-ethoxy-4, of 3 methoxv h l -1 .17]- 5-dihydrothiazolo-[5',4'-16,17]-A -estratriene were A -estratetraene having a melting point of heated under vacuum for 1 minute at a temperature of 285 C. were obtained. 200 C. to obtain 40 mg. (a yield of 90%) of S-methoxy- This compound is not described in the literature. z'- i hi l 534-1637 1. .5 I L t t ne Example II. Preparation of 3-methoxy-2'-amino-thia- 50 havmg ameltmg pomt of 275 280 zolo-[5,4-l6,17]-A -estratetraene pharmacological data Step A: Preparation of 3-methoxy-2-amino-4'-ethoxy- Hypophysialinhibitory activity 4,5' dihydrothiazolo [5,4'-16,17] A estra- Many couples of female rats, each couple being sisters, triene.1.5 gm. of 3-methoxy-16 a-bromo-A -estrawere united parabiotically. One of the animals was castriene-17-one prepared according to the process described trated and treated daily over a period of 10 days, starting by W. S. Johnson et 211., J.A.C.S., vol. 79, page 2005 on the day following the pairing. The animals were (1957), were introduced into 15 cc of ethanol and after sacrificed on the 11th day. The genital organs were re- 625 mg of thiourea were added thereto, the reaction mixmoved and weighed. The castrated rats received by oral ture was heated at reflux for 24 hours with constant agi- 6O administration 6.25 and 12.507 per day of 3-methoxy-2'- tation Then, the reaction mixture was poured into an amino-thiazolo-[5',4-16,l7]A -estratetraene disaqueous solution of sodium bicarbonate and extracted solved in olive oil mixed with 5% benzylic alcohol. The with ethyl acetate. The extracts obtained were washed experiment included control animals parabiotically with saturated aqueous sodium chloride, dried and evapunited; a castrated animal parabiotically paired with a orated to dryness. The residue formed was dissolved in whole animal and whole animals not parabiotically ether, treated with animal charcoal and filtered. 2 cc. of united. Tablelsummarizes the results obtained.

TABLE I Castrated donor rat Intact receiver rat Groups Daily Aver. body weights Aver. body weights doses in v in gm. Uterus, iu gm. Ovaries, Uteru mg. M mg. mg. Initial Final Initial Final Free controls 0 67 97 26.18 83.28 United controls 0 74 s7 s4. 32 72 92 159. 22 146. 39 3-methoxy-2-amin0-thiazolo-[5,4-16,17]1,3,5(10),10- 6. 25 73 as 63. 6s 66 as 141. 46 169. 9a cstratetraene. 12. 50 74 64. 31 69 75 23. 30 93. 5s

The results of Table I show that the product of the invention possesses an important inhibitory hypophysial activity at a dose of 12.50 Moreover, its estrogenic action is slight as can be seen from the increase in weights of the uterus of the castrated female animal in the test and by the equivalent of the rat-unit, determined on the castrated rat according to the Allen and Doisy test, which dose, orally adminstered, amounts to about 5 mg.

Various modifications of the compositions and method of the invention may be made without departing from the spirit or scope thereof and it is to be understood that the invention is to be limited only as defined in the appended claims.

We claim:

1. A 2' amino-thiazolo [5,4 16,l7]-A estratetraene of the formula wherein R is selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms and phenyl alkyl with 1 to 2 alkyl carbon atoms.

2. The compound of claim 1 wherein R is methyl.

3. A process for the preparation of a 2'-aminothiazol0- [5,4 16,17]-A -estratetraene of claim 1 which comprises reacting a compound of the formula wherein R has the above definition and X is an aor 18- halogen selected from the group consisting of chlorine, bromine and iodine with thiourea in a lower alkanol having 1 to 8 carbon atoms to form the corresponding estratetraenes.

4. The process of claim 3 wherein R is selected from the group consisting of methyl, ethyl, propyl and n-butyl.

5. The process of claim 3 wherein R is benzyl.

6. The process of claim 3 wherein the lower alkanol is selected from the group consisting of methanol, ethanol and tert.-butanol.

7. The process of claim 3 wherein the halogen is selected from the group consisting of bromine and iodine.

8. The process of claim 3 wherein the lower alkanol is selected from the group consisting of methanol and ethanol and the resulting intermediate 3 OR 2' amino- 4 alkoxy 4',5" dihydrothiazolo [5',4'-16,17]- A estratriene wherein the 4-alkoxy is derived from the said lower alkanol is reacted under alkaline conditions to form the said 2' amino thiazolo-[5,4'- l6,l7]-A -estratetraene.

9. The process of claim 3 wherein the lower alkanol is selected from the group consisting of methanol and ethanol and the resulting intermediate 3 OR 2 amino- 4' alkoxy 4',5' dihydrothiazolo [5,4 16,17] A -estratriene wherein the 4'-alkoxy is derived from the said lower alkanol is heated under vacuum to form the said 2' amino thiazolo [5',4-16,17]-A estratetraene.

10. A 2 amino 4' alkoxy 4,5 dihydrothiazolo- [5',4-16,17]-A -estratriene of the formula wherein R is selected from the group consisting of hydrogen, alkyl of l to 8 carbon atoms and phenylalkyl having 1 to 2 carbon atoms and R is derived from a primary lower alkanol.

11. A compound of claim 10 wherein R is methyl and R is ethyl.

12. An anti-hypophysial composition comprised of at least one 2 amino thiazolo-[5,4'-16,l7]-A estratetraene of claim 1 and a major amount of a pharmaceutical carrier.

13. A composition of claim 12 wherein R is methyl and the composition contains 1 to 10% of the said estratetraene.

14. A method of curbing excessive hypophysial activity in warm-blooded animals which comprises administering to warm-blooded animals a safe and effective amount of at least one 2' amino thiazolo [5,4' 16,17]- A -estratetraene of claim 1.

15. The method of claim 14 wherein R is methyl.

References Cited Robinson et al., J. Med. Chem, pp. 793-795, November 1963.

HENRY A. FRENCH, Primary Examiner. 

1. A 2''-AMINO-THIAZOLO-(5'',4''-16,17)-$1,3,5(10),16-ESTRATETRAENE OF THE FORMULA
 14. A METHOD OF CURBING EXCESSIVE HYPOPHYSIAL ACTIVITY IN WARM-BLOODED ANIMALS WITH COMPRISES ADMINISTERING TO WARM-BLOODED ANIMALS A SAFE AND EFFECTIVE AMOUNT OF AT LEAST ONE 2''-AMINO-THIAZOLO-(5'',4''-16,17)-$1,3,5(10),16ESTRATETRAENE OF CLAIM
 1. 